Fibroblast growth factor receptors (FGFRs) are a family of tyrosine kinase receptors (e.g., FGFR1, FGFR2, FGFR3 and FGFR4) that bind and are activated by members of the fibroblast growth factors (FGFs) (see, e.g., Horton et al., Lancet (2007), 370(9582):162-72; Ornitz and Marie, Genes & Dev. (2002), 16: 1446-1465).
Achondroplasia (ACH) is the most common form of short-limb dwarfism. Characteristic features of achondroplasia include a short stature, an average-size trunk, short arms and legs with particularly short upper arms and thighs, limited range of motion at the elbows, and an enlarged head (macrocephaly) with a prominent forehead (see, e.g., OMIM 100800). About 80 percent of achondroplasia cases result from a mutation in the fibroblast growth factor receptor 3 (FGFR3) gene. There are also a number of other skeletal disorders associated with mutations in FGFR3 and other FGFRs.
Heat shock protein-90 (Hsp90) is a eukaryotic chaperone that ensures proper folding of proteins. Hsp90 preferentially stabilizes mutant kinases involved in various tumors, and mutant kinases are more sensitive to the inhibition of Hsp90 than wild-type kinases (see, e.g., Citri et al., Embo J., 21: 2407-17 (2002); Germano et al., J Biol Chem 281: 21710-9 (2006)).